Thursday, March 13, 2025
3/13/2025
PROJECT SUMMARY/ABSTRACT Inflammation is the body's response to tissue damage, including brain tissue after stroke. Stroke is one of the leading causes of death and disability, affecting more that 795,000 Americans per year. A majority of strokes are ischemic strokes, where blood flow to the brain is obstructed. Most therapeutic interventions restore blood flow, but these therapies have a limited time frame in which they are effective. Moreover, some patients do not improve even with blood flow restoration. One likely explanation for the limited therapeutic benefit of blood flow restoration after stroke is the secondary damage caused by the acute inflammatory response. This is the so-called, “ischemia/reperfusion (I/R) injury.” Therefore, further understanding and characterization of the inflammatory response to stroke is critical to the development of new therapeutic interventions. Following an ischemic stroke, brain blood vessels respond to inflammatory signals and recruit leukocytes to the area of damage. Neutrophils (PMN) are the earliest responders to tissue damage in the central nervous system (CNS). Like other leukocytes, PMN interact with adhesion molecules on the endothelial cell surface and undergo transendothelial migration (TEM), squeezing between endothelial cells and migrating into the tissue bed. TEM is important because it is essentially irreversible, committing the cell to extravasation. Our research shows inhibition of TEM significantly reduces stroke infarct size in acute stroke, however the mechanism connecting TEM blockade to a reduction in infarct size is unknown. We show that blocking TEM alters the spatiotemporal distribution of leukocyte infiltration and extravasation across the ischemic core and penumbra but does not change the total number of leukocytes recruited to infarcted region. Analysis of the leukocyte composition showed PMN are the major infiltrating leukocyte type in acute stroke. These findings suggest that modulating PMN infiltration pattern rather than reducing total leukocyte recruitment may have a protective effect in stroke. We seek to understand the mechanisms by which myeloid cell TEM blockade results in reduced stroke infarct size and the effect of specifically interfering with PMN extravasation on stroke outcomes. To understand effect of TEM blockade following I/R, our first aim will identify how inhibition of TEM during I/R injury in acute stroke alters the immune landscape of the stroke microenvironment. Our studies will identify differences between in leukocyte types over time across ischemic brain regions and differences in the cytokine profile due to TEM blockade. Our second aim will determine the therapeutic effect of blocking leukocyte extravasation in comparison to selective PMN depletion following I/R. Our studies will be conducted at different time points after reperfusion, identifying the effect of inhibition on brain pathology, and mouse motor function. PMN extravasation will be inhibited through two methods: use of TEM-blocking antibodies and the selective depletion of PMN. Completion of these studies will provide insight into the mechanisms regulating PMN response to I/R injury and potentially identify a therapeutic intervention that can be used at the relevant time frame.
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